The remodeling of bone is an ongoing process consisting of bone formation and bone resorption. In healthy subjects, there is a normal balance between bone formation and bone resorption which maintains skeletal mass. Most of the bone surfaces are not active, i.e., are not involved in either bone formation or resorption, instead, there are active surfaces distributed randomly throughout the skeletal system where formation and resorption are locally coupled as units. Resorption areas are covered by osteoclasts, which are cells that resorb and remove osseous tissue, and bone formation surfaces are covered by active osteoblasts, which are cells that form osseous tissue.
Bone disorders affect millions of individuals everyday causing painful and debilitating symptoms including bone fractures. Of particular interest are bone disorders that are caused by abnormal osseous tissue homeostasis, which eventually leads to a loss of bone mass. The abnormal osseous tissue homeostasis is the result of an imbalance between bone formation by osteoblasts and bone resorption by osteoclasts that leads to a net bone resorption. The resulting decreased bone mass can lead to many different bone disorders, including osteopenia, osteoporosis, and other well known bone disorders.
One particular bone disorder, osteoporosis, is commonly observed in postmenopausal women and in the elderly and is characterized by, low bone mass and microarchitectural disruption that results in fractures with minimal trauma. Low bone mass is caused by an abnormality or disturbance in calcium homeostasis. Subjects afflicted with osteoporosis often experience fractures of the wrist and spine, and femoral fractures are common with respect to the elderly. The pathology of this disease is understood to involve a number of physical, hormonal, and nutritional factors acting alone or in combination.
Available treatment for osteoporosis is limited to improvement of dietary intake and physical activity, or use of pharmacological agents that reduce the net resorption of calcium from bone. The reduction of net resorption can be achieved either by decreasing the rate of bone resorption or by promoting bone formation. Current drugs available for osteoporosis therapy operate by preventing or inhibiting bone resorption, but this therapy has natural limitations as bone metabolism reaches a steady-state level. Once the steady-state level is achieved, there is no further increase in bone formation and bone mass density reaches a plateau. Existing anti-resorption agents useful in treating osteoporosis or increasing bone mass density include: calcium salts, e.g., calcium carbonate, vitamin D and its analogs, estrogen, calcitonin, and bisphosphonates. There are also bone-forming agents useful for treating osteoporosis and increasing bone mass density including fluoride, androgen, and parathyroid hormone. These agents have been found to be successful in maintaining bone mass density, but there is little success towards significantly improving the bone mass density in a subject with a bone disorder.
Another particular bone disease is a non-union fracture, which is a fracture which due to various factors fails to heal in a normal time period and requires some form of intervention to stimulate healing. Factors known to contribute to the occurrence of non-union fracture include smoking, diabetes and age. While some non-invasive treatments exist for this disorder, e.g., electrical stimulation or specialized braces, the treatments may not always be applicable to the particular fracture and even when applicable, may not result in success. Other treatments involve invasive measures, i.e., some type of surgery, such as removal of dead tissue, insertion of internal brace (either a rod, plate or screw), or bone graft. In some cases amputation may be necessary to prevent further injury to a subject presenting with a non-union fracture. Even if such intervention provides some success, the existing intervening treatments are typically inconvenient, expensive, often times painful, and can result in physical scarring or impairment.
Calmodulin is a calcium-dependent regulator protein that functions as an intracellular intermediary for calcium ions and is known to activate a number of enzymes involved in fundamental cell processes, e.g., protein phosphorylation, contractile processes, and metabolism of cyclic nucleotides, glycogen and calcium, as well as in other metabolic reactions. Calmodulin can also act as a 3′5′-cyclic nucleotide phosphodiesterase, which hydrolyzes the phosphodiester bond of a 3′5′-cyclic nucleotide to form the corresponding nucleotide.
There still remains a need for a treatment or preventive measure to increase the bone mass density in a subject suffering from a bone disorder, particularly osteoporosis. Further still, there remains a need for a treatment to heal non-union fractures without the need for invasive measures or amputation.